By Y. Armon. Western Maryland College. 2018.

Data from population- facility with a skilled attendant discount linezolid 600 mg on line. Most Counseling should not only focus on health issues studies dealing with the proportion of male or but also on financial issues such as transport costs female discordant partners find that the ratio is and costs of artificial feeding options purchase linezolid 600mg visa. The risk of HIV infection for the other must include the following: partner depends on factors such as co-existing STIs effective linezolid 600mg, male circumcision, viral load and disease progres- • Assessment of eligibility for ART and pre- sion of the infected partner and whether the latter conception initiation of ART. If your hospital is tile days able to check for viral load, this should be <50 • Male circumscision in the uninfected male partner copies. A high CD4 count, however, is a surrogate • Pre-exposure prophylaxis with ART for the un- marker for low viral load and is ok for monitoring 13 infected partner. If the woman is on ART, her regimen should Sero-negative partners should be tested for not contain efavirenz as this drug has teratogenic HIV every 3 months while trying to conceive. If 208 HIV/AIDS-related Problems in Gynecology conception and delivery are successful, their chil- 11–15 presuming that the woman has a regular dren should also be tested as mentioned above. To reduce unnecessary exposure a complete sterility work-up as described in Chapter 16 on Female discordance If the woman is HIV positive and both partners should be done before hand and any the man not, pregnancy should not be attempted necessary treatment should already be accomp- naturally where insemination is available and the lished. There is evidence that pre-exposure prophy- couple should use condoms during intercourse at laxis might decrease the risk for the uninfected all times. The cycle of the woman should be moni- female partner and several studies are still ongoing. The couple should be taught nation with semen using a ‘swim-up’ technique as how to inject sperm into the woman’s vagina using described in Chapter 16 can be considered as the a syringe (without needle). During the fertile days number of lymphocytes in the swim-up will be sig- of the woman (usually cycle days 11–15) the man nificantly reduced. If PCR testing for viral parts is should ejaculate in a pot or a condom (without done in your facility, you can do this on the washed spermicide) and draw the content into the syringe. If PCR is negative, the risk of HIV trans- Either he or the woman should inject the sperm mission is even smaller. If by this method the woman doesn’t conceive after 6 months, further subfertility assessment of both partners should be SERVICE INTEGRATION OF HIV/AIDS done as described in Chapter 16. AND REPRODUCTIVE HEALTH SERVICES Male discordance If the man is HIV-infected and his Service integration means that staff, knowledge and female partner not, the issue is far more compli- capital resources are shared in order to strengthen cated. Studies from Uganda and Ghana suggest that health services as a whole. HIV/AIDS constitutes a transmission rates in sero-discordant couples might humanitarian crisis with its high burden of disease be as low as 0. Overall as you can see, the risk of ever, HIV/AIDS is only one among other diseases transmission is higher in male discordance and the that kill the poor. In 2001 it was responsible for couple and especially the woman needs good and 5. As financial resources from continuous counseling on her risks. Intrauterine in- governments and donors are limited, funds for the semination after washing semen has a low risk of fight against HIV/AIDS are often reallocated from transmission, but is not widely available yet. Clear- other programs and unfortunately implementation ly, the only procedure with no risk of transmission of HIV/AIDS activities has been mostly carried out in low-resource settings is adoption or donor in a vertical way, meaning that special programs sperm. Resorting to a husband’s male family mem- were created with special equipment and special bers for conception in case the husband is suspected positions which do not take into account that there to be infertile is an accepted solution in many cul- is already a health system with equipment and staff tures and should not be omitted as an option pro- taking care of routine healthcare such as primary vided the donor is HIV negative and willing to be healthcare (PHC) and MCH. As a 209 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS consequence the same staff who was responsible for HIV/AIDS you should look at who else could basic healthcare is now working in HIV/AIDS profit from community-based (palliative) care, such projects and an already weak PHC system is thus as people with cancer or paralysis or tuberculosis. Service integration of HIV/ Another example is the scaling up of PMTCT AIDS and sexual and reproductive health services is activities in an area were most deliveries take place important and obvious: in the community with traditional birth attendants. If you don’t tackle the rate of facility-based • 55% of PLWHA are women worldwide. If you unintended pregnancies including HIV-positive 11 integrate PMTCT activities and maternal health women. Here are some more examples of service inte- These services do not only share their clients, they gration from practical experience that merit a have common objectives as well: further look: • Safe delivery with knowledgeable, skilled • Infection prevention and control in the hospital. For • Involvement of the public and of patients (tradi- example, the weak point of many PMTCT pro- tional healers/birth attendants, religious leaders, grams is that the focus was put initially on the child, male partners). As a consequence referral of • Safe blood provision (from opportunistic dona- HIV-positive mothers to a CTC after delivery or tions to voluntary donations). ART often didn’t take place and the women were • Family planning services. Given the fact that, as mentioned above, the mortality of HIV-negative infants is higher when the mother is sick, this will diminish REFERENCES the benefits from PMTCT for the HIV-exposed 1. Nature 2001;410:868–73 facility you should assess additional activities you 3. For example, if you are planning HIV-infected mothers in Africa: a pooled analysis. Gynäko- living with HIV/AIDS and their children in resource- loge 1999;32:540–51 constrained settings. Sero-discordant couples in five African incidence of cervical cancer in women with HIV.

CR was achieved after superiority for CM over RT alone treatment in NLPHL patients surgery in 86% of patients trusted linezolid 600 mg, all with stage IA disease cheap linezolid 600 mg fast delivery. At a median follow-up of 43 months purchase linezolid 600 mg fast delivery, the this retrospective trial, stage IA/B or IIA patients who received RT estimated overall FFP was 67%. More than 60% had stage I disease and the 10-year of 52 patients with stage IA disease without bulky disease with surgical PFS showed favorable outcomes for CM treatment at 91% versus total resection alone. These investigators found a 17% relapse rate at a 65% and raised the question of whether all early-stage HL patients median of 10 months, with a 2-year estimated event-free survival of should be treated similarly. Although follow-up overall for both of these trials was relatively short, if these Rituximab monotherapy. Given the high levels of activity seen results remain durable, with longer follow-up, this would add further for the anti-CD20 antibody rituximab from trials conducted in the evidence to this as a potential curable treatment modality. The 28 patients evaluated; the 3-year PFS was 81%, suggesting that rarity of the diagnosis of advanced-stage NLPHL generally restricts long-term results remain superior with CM or RT, but opening the ability to perform large comparative trials, so the best evidence further potential for rituximab-based combination treatments in the for determining preferred management options typically comes frontline setting. For this treated newly diagnosed patients with initial 4 weekly infusions reason, treatment guidelines such as those from the National rituximab at a dose of 375 mg/m2 with potential for maintenance Comprehensive Cancer Network list multiple chemotherapy options therapy every 6 months for 2 years. In total, 19 newly diagnosed such as CVP, CHOP (cyclophosphamide, hydroxydaunorubicin, patients have been treated and 68% have stage I/II disease. Ten vincristine, prednisone/prednisolone), and ABVD plus or minus patients received limited treatment and 9 had treatment that rituximab as valid options (Table 2). The ORR was 100% with a CR/ unconfirmed CR (CRu) rate of 63%. Late relapses were seen and at cHL-directed chemotherapy. The GHSG analyzed outcomes for 5 years the estimated PFS is 52% while at 10 years it is 35% with no the 8298 HL patients treated on their HD4 to HD12 trials. Of the significant difference noted for those who did or did not receive patients enrolled, only 5% had NLPHL. Limited versus extended rituximab treatment for relapsed NLPHL Treatment Response rate Long-term outcomes Reference Weekly infusions 4 ORR: 94% Median follow-up: 63 mo 33 CR: 53% Median TTP: 33 mo Median OS: Not reached Weekly infusions 4 (limited) versus weekly infusions 4 ORR: 97% Median follow-up: 60 mo 43 and every 6 mo for 2 y (extended) CR (limited): 56% Median FFP (limited): 24 mo CR (extended): 88% Median FFP (extended): not reached TTPindicatestimetoprogression. Although at a median follow-up of 50 NLPHL patients with relapsed or refractory disease. A total of 21 months, the FFTF for advanced-stage NLPHL and cHL was similar patients were treated and, with central pathology review, the at 77%, there was a higher rate of relapses at 1 year or greater for diagnosis of NLPHL was confirmed in 15 patients; 2 were those with NLPHL, at 7. In those with confirmed NLPHL, the ORR was 94%, with 53% CRs. At a median Data have also been presented from both the Cancer and Leukemia follow-up of 63 months, the median time to progression was 33 Group B (CALGB) trials 8251 and 8952 and the Dana-Farber months (Table 3). Seven total patients were alkylating agent–containing regimen mechlorethamine, vincristine, treated, with all but 1 patient having cHL. Patients were treated with procarbazine, prednisone (MOPP) or the hybrid regimen MOPP/ single-patient-specific doses of 450 mg of tositumomab and 131I ABVD. Of the 37 NLPHL patients treated across these trials, there tositumomab. Overall, was a 2-fold lower rate of disease progression or relapse in those the most common adverse events, as anticipated, were cytopenias. These investigators proposed that alkylating agent–based Transformation to aggressive B-cell lymphoma. Overall, a regimens such as MOPP or cyclophosphamide-based therapies higher risk of transformation to aggressive B-cell NHL exists for might be preferred. One of the largest series was published by the BCCA group. We at UTMDACC transformation to an aggressive B-cell NHL at a median of 8. Of An increased risk of transformation was seen in those with 83 patients referred with NLPHL, we confirmed NLPHL diagnoses advanced-stage disease and splenic involvement at diagnosis of in 63 patients. Of the 13 patients with transformation, 6 patients received patients, who received treatment regimens including mitoxantrone, R-CHOP chemotherapy, with 6 patients receiving R-CHOP or other vincristine, vinblastine, prednisone (NOVP), ABVD plus or minus rituximab-containing chemotherapy regimens, followed by high- rituximab, and R-CHOP. Twelve advanced-stage patients received dose chemotherapy and autologous stem cell transplantation (ASCT). ORR with R-CHOP was 100%, with a 90% CR rate, and CR in those with transformation was achieved in 69% and the no relapses or transformations have been seen at a median follow-up 10-year PFS and OS rates were 52% and 62%, respectively. Given the known near outcomes, patients from the Mayo series had a lower rate of 100% level of CD20 expression on L&H cells, 2 key trials by the transformation at 8%, with transformation occurring earlier and a GHSG and Stanford first evaluated the role of rituximab in treating median time to transformation of 2. Patients were treated with 4 weekly favorable, with a 5-year OS for the transformed lymphoma patients doses at 375 mg/m2. This trial was then modified to allow for extended maintenance rituximab treatment, with patients repeat- Although the clinical factor of advanced-stage disease at diagnosis ing the 4 weekly infusions every 6 months for 2 years. A total of 16 is a risk factor for transformation, the pathological risk factors for patients, 7 with relapsed disease, received extended therapy.

Further reanalysis of this landmark dataset buy discount linezolid 600 mg line, progression-free and overall survival purchase linezolid 600 mg otc. What is missing at ( 1% by 12 months) were noted to be associated with superior this time are crucial data to prove the value of intervention at 3 or 6 event-free survival and the lowest rates of progression to advanced months; that is purchase linezolid 600mg fast delivery, bringing response back on track and which strategy phase disease. This reanalysis highlighted the controversy regarding to do so. Planned and ongoing trials have incorporated this pivotal the timing and added value of MMR, noting that those with 0. Loss of CyR was noted to be more likely (26% vs 3%) for those without the added margin of MMR at 18 months. Arrows represent individual patient initial Bcr-Abl1 transcript level reduction. EMR early molecular response; CHR complete hematologic response; PCyR partial cytogenetic response; CCyR complete cytogenetic response; MMR major molecular response; MR molecular response (3,4,4. Anderson group of a large number of functional cure only a glimmer of hope, patients early in the TKI era imatinib and second-generation TKI-treated chronic phase CML aimed for PCR negative, and in Canada even formed a “Zero Club” patients critically examined the impact of ‘undetectable’ molecular for those patients having an undetectable transcript level at least response (beyond MR4. As longer-term imatinib patients and survival, this was not sustained when adjusting for lead-time bias increasing numbers of patients treated with nilotinib and dasatinib (greater time required to achieve undetectable status) by landmark gained such depths of remission, the significance of CCyR and analysis; in addition, the notion of ‘sustained MR4. A second analysis by the remission morphed into response milestones. The current reality of Bordeaux/Lyon group examined the impact of CMR (MR4. So if not of eradication, what of controversial; the long-term follow-up of increasingly vast numbers deep molecular remission and its benefits? Defining the importance of molecular response beyond MMR has What might functional cure mean for CML? One clear dilemma is that such response cancer treatment based on several principles: (1) initial therapy with thresholds lie at or below the limit of detection of the majority of oral targeted therapy; (2) maintenance of initial ‘induction’ or assays used to assess patients’ response, both in commercial and ‘primary’ therapy in the presence of response indefinitely (at least academic settings. The importance placed on deeper molecular based on current algorithms); and (3) the forecast of ability to response is based on the fact that such response is sought and achieve a meaningful deep remission potentially equitable with a deemed necessary for consideration for treatment interruption or ‘functional cure’ in a significant minority to nearly half of patients. Points of action over time in CML based on NCCN, ELN, and possible future guidelines Time point NCCN ELN The future? Therefore, the findings of initial studies have been remarkably similar: patients view of how deep and how stable one’s remission need be before relapse rapidly (nearly exclusively in the first 6 months of treatment consideration of TFR has evolved. It embraces the somewhat cessation) if it occurs; success of treatment cessation is 40–50%; unique feature of CML under TKI therapy, that someone may be and predictors of success with cessation appear to be lower Sokal “cured” while still with evidence of disease [a concept also risk at diagnosis and longer duration of treatment. What has begun proposed in patients with t(8:21) fusions identified in long term to broaden is the scope of discontinuation trials, now encompassing remission after AML38]. Large efforts as well The lessons learned over the last 15 years, during which time continue on behalf of pharmaceutical partners, particularly No- TKIs evolved from phenomenal yet uncertain to entrenched and vartis, in which an array of discontinuation trials are ongoing to unprecedented regarding their efficacy, have been that timely query the benefits of primary nilotinib therapy or switch to nilotinib declines in Ph clonal burden below relevant thresholds anchored in after imatinib with regard to TFR. Response is typically migrated from the initial trials’ threshold of molecular relapse “biphasic” (rapid decline followed by slower decline) and in a sense (detectable disease generally in the 4- to 4. Although, at face value, this may portend that “failure” of as demonstrated by the preliminary data of ponatinib’s activity in the experiment of cessation may carry with it a 1. Therefore, as long as early milestones are met, therein, several studies have addressed the pragmatic reality of declining disease is acceptable. As noted above, caution is advised patients’ MRD, its stability, and consideration for TFR trials. It in calling response “failure” too early, such as in the case of may be that the stability of deep remission may have little to do seemingly inadequate early transcript reduction based on black and with the success of treatment cessation; in the According to white thresholds (10% IS at 3 months), because individualization of STIM (A-STIM) trial, patients who discontinued from a stable response and accounting for initial disease burden may change CMR and an ‘unstable CMR’ had equal chances of success. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed In essence, disease burden in CML is too much if it is permissive chronic myeloid leukemia: an analysis from the International Random- ized Study of Interferon and STI571 (IRIS). Increasing understanding into the nature of stem cell transcripts in chronic myeloid leukaemia patients in complete remission biology and leukemogenesis, described by many as an accumula- using the polymerase chain reaction and nested primers. Absolute quantitative focus away from the quantity of residual disease but more on the detection of ABL tyrosine kinase domain point mutations in chronic quality of the remission. It may be that the benefit of better CML myeloid leukemia using a novel nanofluidic platform and mutation- therapy is a result, not of eliminating more of it, but of specific PCR. Molecular remission in chronic doing so expeditiously. It is unsettling to patients and dissatisfy- myeloid leukemia patients with sustained complete cytogenetic remis- ing to practitioners, but it appears that the “little” disease sion after imatinib mesylate treatment. BCR-ABL messenger RNA too much as stable responses are the expectation and treatment- levels continue to decline in patients with chronic phase chronic free remissions appear to be a potential reality for many. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: Disclosures 2013. Conflict-of-interest disclosure: The author has consulted for Ariad, 16. International randomized Pfizer, Bristol Myers Squibb, and Novartis Oncology. Off-label study of interferon vs STI571 (IRIS) 8-year follow up: sustained drug use: None disclosed. Mauro, MD, Memorial Sloan Kettering Cancer Center, 17.

Manu- tumor-antigen-specific T cells in CLL and other approaches are factured T cells originally derived from peripheral or umbilical cord required purchase 600mg linezolid visa. The first involves the gene transfer of TCRs with known blood can then be stimulated by these APCs to enable the expansion specificity into autologous or allogeneic T cells cheap 600 mg linezolid with amex, which are then of clinical grade CD19-specific T cells linezolid 600 mg otc. A second strategy involves the use studies, human anti-CD19 CAR T cells containing the costimula- of the single chain variable fragment from an antibody molecule fused tory domain CD137 (4-1BB) were significantly more effective, 154 American Society of Hematology showed longer survival times than cells expressing CARs contain- inducing expression of costimulatory and adhesion molecules on the ing the CD28-signaling domain and were less likely to trigger the transduced cell, increased expression of CD40L in the CLL induction of a “cytokine storm” and differentiation of Tregs. The microenvironment can activate other B cells even if they were not use of anti-CD19 CAR T cells incorporating a CD137-costimula- transfected. An early clinical trial investigated the effects of tory domain resulted in the achievement of CR in a case of a heavily infusions of autologous tumor cells that had been transduced ex vivo pretreated patient with refractory CLL. This treatment was well tolerated after infusion and the CAR T cells had started to express molecules and the patients did show some peripheral blood and lymph node associated with a “central memory” phenotype, which is important responses. However, some of the patients developed antibodies in maintaining robust and persistent antitumor immune responses. As described above, T cells from CLL patients have pro-apoptotic state in the circulating CLL B cells, with increased profound defects in proliferative capacity and cytotoxicity. How- expression of the pro-apoptotic molecules CD95, DR5, p73, and ever, they can be successfully transfected and induced to proliferate BCL-2 interacting domain (BID) and reduced levels of the antiapo- in vitro and proceed to rapidly expand and cause extensive tumor ptotic molecule MCL-1. Significantly, these findings were also lysis after infusion back into patients. There are several potential observed in patients with deletion of chromosome 17p53 and explanations for this apparent paradox. First, simply removing intranodal injection was safe and induced clinical responses. Lenalidomide Second, the strong pro-proliferative signals provided by anti-CD3/ Lenalidomide is approved for the treatment of multiple myeloma anti-CD28 beads in vitro and binding of the CAR to CD19 in vivo and 5q myelodysplastic syndrome. It is not licensed for use in may overcome more subtle functional defects. Third, proliferative CLL, but is being evaluated in clinical trials in CLL, where it has stimuli applied in vitro could “select out” cells that have retained the shown clinical activity alone,55,56 in combination with rituximab,57 ability to proliferate, leading to restoration of global proliferative and as consolidation after immunochemotherapy. A final potential explanation is the effect of the CAR of action in CLL appears to be primarily by enhancing antitumor construct itself. A reduction in proliferative capacity is associated immunity. The be a key component of this agent’s activity in CLL. Understand- function with immunomodulatory agents may therefore be useful to ing any such interactions may be important for enhancing the enhance T-cell-mediated responses such as vaccines or adoptive durability of CAR T-cell activity by promoting the formation of T-cell transfer. A correlative study that accompanied a clinical report of CAR T cells Conclusions in CLL noted high expression of CD45RA, PD-1, and CD57 at day New treatments are resulting in improved survival for younger CLL 169 after infusion, which may reflect the emergence of T-cell patients, but older patients remain a particular challenge. There has exhaustion and incipient loss of function. Allogeneic HSCT remains potentially curative, but is analogous to Bruton’s X-linked agammaglobulemia. However, the associated with significant morbidity and mortality. Our increased potential of targeting alterative tumor antigens, in particular those understanding of the immunobiology of CLL is now starting to not expressed in normal tissues such as the oncofetal antigen translate into a wide variety of therapies that target the immune ROR1,38,51 other costimulatory approaches, and the engineering of microenvironment and have the potential to use patients’ own other cell types with CARs, such as NK and NKT cells, means that activated or modified T cells to induce antitumor control. Further- this remains an extremely exciting area of research. This “eviction from the niche” may allow A further area of intense investigation was stimulated by the for increased T-cell accessibility in addition to enhancing the observation that patient T cells show reduced expression of CD154 susceptibility of the tumor cells to immunotherapeutic approaches, (CD40L). The CD40/CD40L axis is critical for B-cell maturation, thereby providing a rationale for novel treatment combinations. CLL B cells have reduced expression of These treatments have the potential to be highly effective, and their CD80 and CD86 and are functionally poor at antigen presentation. Several strategies have been developed to capitalize on the Disclosures activating effect of CD40L. One such strategy was to use adenoviral Conflict-of-interest disclosure: J. In addition to an advisory committee for Pharmacyclics and Celgene, has received Hematology 2013 155 research funding from Celgene, and has received honoraria from on the VH gene mutational status. Early autologous ment that are not yet approved and their potential future use. Addition of in patients with B-cell chronic lymphocytic leukemia and rituximab to fludarabine and cyclophosphamide in patients with determines the total CD4 T-cell repertoire. Minimal residual disease patients exhibit features of T-cell exhaustion but retain capacity quantification is an independent predictor of progression-free for cytokine production. Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG.

There were no clear differences in rates of other adverse events purchase linezolid 600mg amex. The trial that compared once-daily with twice-daily preparations of oral morphine was 25 also rated poor quality for adverse events (Evidence Table 4) linezolid 600 mg fast delivery. Serious adverse events (not defined) occurred in 6 enrolled patients cheap linezolid 600 mg visa, but the rates of serious complications were not reported for each treatment group. This trial found a significantly higher rate of constipation in patients on once-daily morphine given in the morning (49%) than twice-daily morphine (29%), but a lower rate of asthenia (1% vs. The overall withdrawal rates in patients randomized to any long- acting morphine preparation ranged from 37% to 45% and withdrawal rates due to adverse events ranged from 23% to 25%. Withdrawal rates in head-to-head trials are shown in Table 6. Although there was a wide range of withdrawal rates across studies, within individual trials there were no significant differences between long-acting opioids. There was no pattern to suggest that any long-acting opioid is associated with a higher overall withdrawal rate or higher rate of withdrawals due to inadequate pain relief than any other long-acting opioid. Withdrawal rates in head-to-head trials of long-acting opioids for chronic noncancer pain Withdrawal Withdrawal due to due to Withdrawal Author N/ inadequate adverse for other Year Duration Long-acting opioid Overall pain control events reasons Transdermal fentanyl 52% (177/338) 5% 37% 10% Allan 683/ 23 Oral morphine 2005 13 months 47% (162/342) 4% 31% 12% (twice daily) 16% Transdermal fentanyl NR 11% NR Allan 256/ (39/250) 24 2001 4 weeks Morphine 9% (21/238) NR 4% NR (twice daily) Oral oxymorphone 28% (22/80) 20% 2. No trials evaluated efficacy of opioid rotation for management of adverse events associated with long-acting opioids in patients with chronic noncancer pain. Indirect evidence Randomized trials We identified 26 placebo-controlled trials of long-acting opioids that reported adverse events 11, 25, 26, 28, 40-50, 52-57, 59-62, 64 (Evidence Tables 2, 3, and 4). With regard to adverse event assessment, all placebo-controlled trials had important methodological flaws. In addition, these trials had heterogeneous study designs, interventions, outcomes, and patient populations, making meaningful comparisons across studies difficult. Included trials generally found a higher rate of adverse events with long-acting opioids compared 44, 50 41 with placebo or active placebo (benztropine and lorazepam ). In trials that assessed adverse 11, 51 events from different doses of a long-acting opioid, higher doses were associated with more adverse events than lower doses. In the trial that compared morphine to gabapentin plus Long-acting opioid analgesics 30 of 74 Final Update 6 Report Drug Effectiveness Review Project morphine, the combination was associated with lower rates of constipation (most likely due to 41 lower doses of morphine) and higher rates of dry mouth (most likely due to the gabapentin). Other adverse events in trials with active placebos were similar. These trials reported wide ranges for adverse event rates even in studies that evaluated the same long-acting opioid at roughly equivalent doses. For long-acting oxycodone at mean 34 39 doses of 40 mg daily, for example, rates of nausea ranged from 15% to 50% in 5 trials (Table 36 11 6). Withdrawal rates due to adverse events ranged from 4% to 32% in these same studies. Given the uncertainty regarding the rate of adverse events for individual long-acting opioids, it is not surprising that these trials show no discernible pattern of 1 long-acting opioid being superior to others for any reported adverse event. Observational studies We identified 14 cohort studies evaluating the safety of long-acting opioids in patients with 11, 25, 40, 69-79 noncancer pain. None were rated good quality for adverse event assessment (Evidence Table 5). Two 77, 78 studies evaluated the comparative risk of constipation from different long-acting opioids and the others assessed one long-acting opioid or did not assess comparative safety. The number of 71 78 patients on long-acting opioids in these studies ranged from 11 to 2095. Eight were 11, 25, 40, 69, 72, 74-76 70, 71, 73, 77, 78 prospective cohort studies and 5 were retrospective cohorts. The 11, 25, 40, 69 72 prospective cohort studies recruited all or some of their patients from completed 11, 25, 40 clinical trials. Three of the prospective cohorts were open-label extensions of clinical trials included in this review. Two large, fair-quality retrospective cohort studies of California Medicaid patients found that the rate of a new diagnosis of constipation was significantly higher in patients prescribed long-acting oxycodone than transdermal fentanyl (adjusted odds ratios, 2. One of these studies also assessed the risk of constipation with long-acting morphine compared with transdermal fentanyl and did not 77 find a statistically significant difference (adjusted odds ratio 1. In these studies, patients on transdermal fentanyl were significantly older, more frequently male, on lower doses of opioids, and more frequently on tricyclic antidepressants. Marked differences in measured confounders suggested a higher risk for residual confounding due to unmeasured or unknown factors. This is important because studies that rely on administrative databases are frequently limited in their ability to measure important potential confounders.

Randomized placebo- controlled trial comparing montelukast and cetirizine for treating perennial allergic rhinitis in children aged 2-6 yr buy linezolid 600 mg low cost. Efficacy and safety of ebastine 20 mg compared to loratadine 10 mg once daily in the treatment of seasonal allergic rhinitis: a randomized cheap linezolid 600mg otc, double-blind buy discount linezolid 600mg on-line, placebo-controlled study. The comparison of cetirizine, levocetirizine and placebo for the treatment of childhood perennial allergic rhinitis. A randomized double-blind placebo controlled study of azelastine nasal spray in children with perennial rhinitis. Double-blind multicenter study on the efficacy and tolerability of cetirizine compared with oxatomide in chronic idiopathic urticaria in preschool children. Prevention of acute urticaria in young children with atopic dermatitis. Comparative study of sensory attributes of two antihistamine nasal sprays: olopatadine 0. Investigation of long-term efficacy and tolerability of azelastine nasal spray in the treatment of perennial allergic rhinitis. Efficacy and tolerability of azelastine nasal spray in the treatment of allergic rhinitis: large scale experience in community practice. Risk of hypospadias in offspring of women using loratadine during pregnancy: a systematic review and meta-analysis. Double-blind, placebo controlled comparison of cetirizine 2HC1 and terfenadine in atopic perennial rhinitis. Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate-to-severe seasonal allergic rhinitis. Spector SL, Shikiar R, Harding G, Meeves S, Leahy MJ. The effect of fexofenadine hydrochloride on productivity and quality of life in patients with chronic idiopathic urticaria. Layton D, Wilton L, Boshier A, Cornelius V, Harris S, Shakir SAW. Comparison of the risk of drowsiness and sedation between levocetirizine and desloratadine: a prescription- event monitoring study in England. Examining the tolerability of the non-sedating antihistamine desloratadine: a prescription-event monitoring study in England. Antihistamines Page 43 of 72 Final Report Update 2 Drug Effectiveness Review Project 127. Pedersen L, Norgaard M, Skriver MV, Olsen J, Sorensen HT. Prenatal exposure to loratadine in children with hypospadias: a nested case-control study within the Danish National Birth Cohort. Increased risk of serious injury following an initial prescription for diphenhydramine. Evaluation of the safety of fexofenadine from experience gained in general practice use in England in 1997. Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. A multicentre, double-blind, parallel, randomized, placebo-controlled study : evaluation of the efficacy and safety of levocetirizine 5 mg and desloratadine 5 mg administered orally as capsules once daily, in the morning, over 2 weeks in patients suffering from allergic rhinitis (AR) [completed]. Study evaluating the efficacy and safety of 5 mg levocetirizine oral tablets, once daily versus 10 mg loratadine oral tablets, once daily for the treatment of seasonal allergic rhinitis (SAR) [completed]. Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis. Salmun LM, Gates D, Scharf M, Greiding L, Ramon F, Heithoff K. Loratadine versus cetirizine: assessment of somnolence and motivation during the workday. Improvements in simulated real-world relevant performance for patients with seasonal allergic rhinitis: impact of desloratadine. Comparative outdoor study of the efficacy, onset and duration of action, and safety of cetirizine, loratadine, and placebo for seasonal allergic rhinitis. Berger WE, Schenkel EJ, Mansfield LE, Desloratadine Study Group. Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Efficacy and tolerability of once-daily 5mg desloratadine, an H1-receptor antagonist, in patients with seasonal allergic rhinitis: Assessment during the spring and fall allergy seasons. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo- controlled study. Effect of a few histamine1-antagonists on blood glucose in patients of allergic rhinitis. Antihistamines Page 44 of 72 Final Report Update 2 Drug Effectiveness Review Project 143. Acute urticaria: clinical aspects and therapeutic responsiveness.

Such statements in these studies lack rigorous definitions of the methods used to monitor for and detect adverse events discount 600 mg linezolid amex. Other studies stated that the incidence of 287 discount linezolid 600mg visa, reporting any adverse events was equal between the treatment and control (placebo) groups 288 generic 600 mg linezolid with visa, 291 285, 292, 295 or reported the incidence of adverse events to demonstrate that point. Treatment- 286 related adverse effects were reported as 8. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid lowering drug when used in special populations or with other medications (drug-drug interactions)? Summary of findings • One study of fluvastatin in children with minimal change glomerulonephritis demonstrated decrease in total cholesterol and reported no side effects. Detailed assessment One study of children with minimal change glomerulonephritis (MCGN) assigned 36 patients to 299 20 mg of fluvastatin or dipyridamole for 2 years. The main study outcome was bone mineral density, for which there was no change over the course of the study. Hematuria decreased significantly, and creatinine clearance, total protein, and albumin increased compared to baseline in the statin group, but not the dipyridamole group. The authors observed no side effects in any of the patients over the treatment period. SUMMARY Table 15 summarizes the level and direction of evidence for each key question. Summary of the evidence by key question Strength of Key question evidence Conclusion ADULTS 1. How do statins and fixed-dose Fair The ideal study would be a double-blind, intention-to-treat combination products containing a randomized trial in which equipotent doses of different statin and another lipid-lowering statins were compared with regard to low-density drug compare in their ability to lipoprotein-lowering, withdrawals, and adverse effects. No reduce low-density lipoprotein studies met these stringent criteria. Are their doses for each statin or Fair-to-good Results of a large number of trials are generally consistent fixed-dose combination product with information from the manufacturer. When statins are containing a statin and another lipid- provided in doses that are approximately equipotent, a lowering drug that produce similar similar percent reduction in low-density lipoprotein percent reduction in low-density cholesterol can be achieved. Is there a difference in the ability Good for most For patients who require low-density lipoprotein cholesterol of a statin or fixed-dose combination comparisons reductions of up to 35% to meet their goal, any of the statins product containing a statin and (see text) are effective. In patients requiring a low-density lipoprotein another lipid-lowering drug to cholesterol reduction of 35% to 50% to meet the National achieve National Cholesterol Cholesterol Education Program goal, atorvastatin 20 mg or Education Panel goals? Atorvastatin 80 mg daily and rosuvastatin 20 mg or more can reduce low-density lipoprotein cholesterol by 50% or more. Based on fair-quality studies, atorvastatin 80 mg daily resulted in 5 to 6 additional percentage points of low-density lipoprotein reduction than simvastatin 80 mg (53% to 54% vs. In head-to-head studies rosuvastatin 40 mg had greater reduction in low-density lipoprotein cholesterol than atorvastatin 80 mg with similar frequency of adverse events. In patients requiring a low-density lipoprotein cholesterol reduction of greater than 50%, the higher doses of ezetimibe-simvastatin at 10/40 mg and 10/80 mg are more likely to meet the National Cholesterol Education Program Adult Treatment Panel III goal than an equivalent high potency statin. How do statins and fixed-dose Fair-to-good When statins are provided in doses that are approximately combination products containing a equipotent for lowering LDL-C, a similar percent increase in statin and another lipid-lowering high-density lipoprotein cholesterol can be achieved. There drug compare in their ability to raise is conflicting evidence about simvastatin vs. Some studies found greater increases in high-density lipoprotein cholesterol with rosuvastatin compared with atorvastatin, while other studies found no difference. How do statins and fixed-dose NA There are no controlled trials comparing equivalent doses of combination products containing a 2 or more statins to reduce the risk of coronary events, statin and another lipid-lowering stroke, or death. Which statins have been shown to Good Patients who have never had CHD: pravastatin (high-risk reduce all-cause mortality? Patients with CHD: simvastatin, atorvastatin Which statins have been shown to Fair-to-good Patients who have never had CHD: atorvastatin (high-risk reduce CHD events? Which statins have been shown to Good Atorvastatin, pravastatin, simvastatin, rosuvastatin (patients reduce strokes? Atorva 10 mg reduced cardiovascular events in a primary prevention trial of patients with diabetes (CARDS), and simvastatin 40 mg reduced cardiovascular events in patients with diabetes (Heart Protection Study). In a subgroup analysis of the LIPS trial, there was a reduction in coronary events (cardiac death, nonfatal MI, CABG, or repeat PCI) with fluvastatin 80 mg in patients with diabetes who had undergone successful PCI. Studies that included people with diabetes had rates of adverse effects similar to other studies. Are there differences in Good (elderly, The benefits of statins have been documented in women effectiveness of statins and fixed- women)-to- and the elderly. There are almost no data about African dose combination products Fair to Poor Americans, Hispanics, or other ethnic groups. In short-term containing a statin and another lipid- (African head-to-head trials, reductions in LDL-C and frequency of lowering drug in different Americans, adverse events with rosuvastatin 10 to 20 mg and demographic groups or in patients Hispanics, and atorvastatin 10 to 20 mg in Hispanic, South Asian, and with comorbid conditions (e. Are there differences in safety of Poor There are no data from clinical trials comparing the safety of statins in different demographic different statins in women, the elderly, or African Americans. A pharmacokinetic study of rosuvastatin conducted in the United States demonstrated an approximate 2-fold elevation in median exposure in Asian subjects (having either Filipino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian origin) compared with a Caucasian control group. Are there differences in the harms Good for Although creatine kinase elevations are common, the risk of of statins or fixed-dose combination statins symptomatic myopathy is low.